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  • γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells

    Author(s)
    Slattery, C
    Jang, Y
    Kruger, WA
    Hryciw, DH
    Lee, A
    Poronnik, P
    Griffith University Author(s)
    Skelly, Deanne
    Year published
    2013
    Metadata
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    Abstract
    Background and Purpose: Albuminuria is an important biomarker of renal dysfunction and is a major mediator of renal damage and fibrosis during kidney disease. The mechanisms underlying albumin-induced renal fibrosis remain unclear. There has been significant interest in γ-secretase activity in tubular epithelial cells in recent times; however, its potential role in albumin-induced fibrosis has not been investigated. Experimental Approach: The primary aim of this study was to examine the role of γ-secretase in albumin-induced fibrotic effects in proximal tubular cells. The effects of increasing albumin concentrations on ...
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    Background and Purpose: Albuminuria is an important biomarker of renal dysfunction and is a major mediator of renal damage and fibrosis during kidney disease. The mechanisms underlying albumin-induced renal fibrosis remain unclear. There has been significant interest in γ-secretase activity in tubular epithelial cells in recent times; however, its potential role in albumin-induced fibrosis has not been investigated. Experimental Approach: The primary aim of this study was to examine the role of γ-secretase in albumin-induced fibrotic effects in proximal tubular cells. The effects of increasing albumin concentrations on fibrosis indicators and mediators in the human HK-2 cell line were examined in the presence and absence of a γ-secretase inhibitor, compound E. Key Results: Treatment with albumin resulted in a number of pro-fibrotic effects, including up-regulation of fibronectin, TGF-β1 and the EGF-R. Interestingly, similar effects were observed in response to treatment with the γ-secretase inhibitor, compound E. Co-treatment of cells with albumin and an EGF-R inhibitor, AG-1478, resulted in significant inhibition of the observed pro-fibrotic effects, suggesting a major role for the EGF-R in albumin-induced fibrotic events. Albumin-induced effects on the EGF-R appeared to be mediated through inhibition of γ-secretase activity and were dependent on ERK-MAPK signalling. Conclusions and Implications: These results provide novel insights into the mechanisms of albumin-induced fibrotic effects in tubular epithelial cells, suggesting important roles for the γ-secretase and the EGF-R. These results suggest that the proposed use of γ-secretase inhibitors as anti-fibrotic agents requires further investigation.
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    Journal Title
    British Journal of Pharmacology
    Volume
    169
    Issue
    6
    DOI
    https://doi.org/10.1111/bph.12214
    Subject
    Pharmacology and pharmaceutical sciences
    Pharmacology and pharmaceutical sciences not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/341922
    Collection
    • Journal articles

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